Addicts have great difficulty resisting cues that have been associated with drug use. Such cues attract their attention, draw them to locations where drugs are located, and motivate continued drug-seeking behavior - often leading to relapse even in the face of an expressed desire to discontinue drug use. Drug cues are thought to acquire incentive motivational properties ("incentive salience") as a consequence of Pavlovian conditioning, whereby previously neutral stimuli acquire conditional stimulus (CS) properties. However, in preclinical studies using rats we have discovered that individuals vary markedly in the extent to which they attribute incentive salience to reward cues. A reward cue may act as a perfectly effective CS, evoking a conditional response (CR) in all animals, but function as a potent incentive stimulus only in some. Only if reward cues act as incentive stimuli do they come to attract, instigate, spur, and motivate, leading to potentially maladaptive behavior. I hypothesize, therefore, that individuals prone to attribute incentive salience to reward cues will have particular difficulty resisting them and will be especially vulnerable to relapse. Indeed, there is considerable variation in the ability of drug cues to instigate drug craving and relapse. Moreover, the degree that such cues increase the desire to take drug is correlated with how much the cue increases dopamine (DA) transmission. In the current application, I propose a series of preclinical studies to investigate individual variation in relapse behavior and its relationship with DA transmission (as measured using fast-scan cyclic voltammetry). This proposal will address the following questions: 1) Does individual variation in the tendency to attribute incentive value to reward cues predict variation in reinstatement to noncontingent drug cues? and 2) Do differences in phasic DA release encode variation in cue-induced reinstatement? These studies have the potential to significantly shift how we think about individual vulnerability to addiction and relapse, and point toward better-targeted interventions. PUBLIC HEALTH RELEVANCE: Addiction is a major public health problem in the United States, and the biggest threat to addicts is a high propensity to relapse. The goal of this project is to use a preclinical model to explore the psychological and neurobiological basis of individual variation in vulnerability to relapse, as this will help identify risk factors that will aid in the development of targeted interventions and treatments.